补阳还五汤通过调节PI3激酶/Rap1/整合素α(IIb)β(3)信号通路改善心肌损伤并减轻血小板活化。
Buyang Huanwu decoction ameliorates myocardial injury and attenuates platelet activation by regulating the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway.
作者信息
Gao Jiaming, Guo Hao, Li Junmei, Zhan Min, You Yue, Xin Gaojie, Liu Zixin, Fan Xiaodi, Gao Qinghe, Liu Jianxun, Zhang Yehao, Fu Jianhua
机构信息
Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Pharmacology of Chinese Materia, Courtyard No. 1, Xiyuan Playground, Haidian District, Beijing, China.
出版信息
Chin Med. 2024 Aug 19;19(1):109. doi: 10.1186/s13020-024-00976-0.
BACKGROUND
Buyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI).
METHODS
Myocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days.
RESULTS
Coronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway.
CONCLUSION
BYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI.
背景
补阳还五汤是一种用于治疗气虚血瘀证的中药。血小板在调节缺血性损伤后的血栓形成和炎症反应中起重要作用，研究表明补阳还五汤通过白细胞介素-17和Toll样受体4途径调节心肌纤维化并发挥抗炎作用，但补阳还五汤在稳定型冠心病中激活血小板的机制尚不清楚。在本研究中，应用左冠状动脉前降支结扎模型来研究补阳还五汤对缺血性心肌梗死（MI）纤维化后调节血小板高反应性和心脏功能的机制。
方法
通过结扎左冠状动脉前降支构建心肌梗死模型。将大鼠随机分为五组：假手术组、模型组、心肌梗死加阿司匹林组（阳性对照组）、心肌梗死加低剂量补阳还五汤组（补阳还五汤低剂量组）和心肌梗死加高剂量补阳还五汤组（补阳还五汤高剂量组），持续给药28天。
结果
冠状动脉结扎显著导致左心室功能障碍，心肌细胞纤维化增加，同时伴有血小板高反应性和高水平炎症因子。补阳还五汤明显逆转心脏功能障碍和纤维化，增加左心室壁厚度，并抑制聚集率和CD62p表达。补阳还五汤恢复了心肌梗死后血小板的线粒体呼吸，同时端粒表达增加，炎症减轻。根据转录组测序结果，我们发现与补阳还五汤治疗组相比，模型组有106个差异表达基因。富集分析筛选出Ras相关蛋白Rap-1（Rap1）信号通路和血小板激活生物学功能。应用定量实时聚合酶链反应和蛋白质免疫印迹法发现补阳还五汤降低了Rap1/磷脂酰肌醇-3激酶-蛋白激酶B/肉瘤蛋白-细胞分裂周期蛋白42基因的表达，并减弱了磷脂酰肌醇-3激酶/Rap1/整合素α（IIb）β（3）途径的过度激活。
结论
补阳还五汤通过磷脂酰肌醇-3激酶/Rap1/整合素α（IIb）β（3）途径减轻炎症和血小板激活，并改善心肌梗死后的心脏功能。
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